Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ6K2XJ)

• DOT Name: Phospholipid scramblase 3 (PLSCR3)
• Synonyms: PL scramblase 3; Ca(2+)-dependent phospholipid scramblase 3
• Gene Name: PLSCR3
• Related Disease: Obesity
• UniProt ID: PLS3_HUMAN
• Pfam ID: PF03803
• Sequence:
  MAGYLPPKGYAPSPPPPYPVTPGYPEPALHPGPGQAPVPAQVPAPAPGFALFPSPGPVAL
  GSAAPFLPLPGVPSGLEFLVQIDQILIHQKAERVETFLGWETCNRYELRSGAGQPLGQAA
  EESNCCARLCCGARRPLRVRLADPGDREVLRLLRPLHCGCSCCPCGLQEMEVQAPPGTTI
  GHVLQTWHPFLPKFSIQDADRQTVLRVVGPCWTCGCGTDTNFEVKTRDESRSVGRISKQW
  GGLVREALTDADDFGLQFPLDLDVRVKAVLLGATFLIDYMFFEKRGGAGPSAVTS
• Function: Catalyzes calcium-induced ATP-independent rapid bidirectional and non-specific movement of the phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer membrane of the mitochondria. Plays an important role in mitochondrial respiratory function, morphology, and apoptotic response. Mediates the translocation of cardiolipin from the mitochondrial inner membrane to outer membrane enhancing t-Bid induced cytochrome c release and apoptosis. Enhances TNFSF10-induced apoptosis by regulating the distribution of cardiolipin in the mitochondrial membrane resulting in increased release of apoptogenic factors and consequent amplification of the activity of caspases. Regulates cardiolipin de novo biosynthesis and its resynthesis.
• Tissue Specificity: Expressed in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, uterus, small intestine and peripheral blood lymphocytes. Not detected in testis, brain and liver.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obesity	DIS47Y1K	Limited	Biomarker	[1]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Phospholipid scramblase 3 (PLSCR3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phospholipid scramblase 3 (PLSCR3).	[5]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Phospholipid scramblase 3 (PLSCR3).	[3]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Phospholipid scramblase 3 (PLSCR3).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phospholipid scramblase 3 (PLSCR3).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phospholipid scramblase 3 (PLSCR3).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phospholipid scramblase 3 (PLSCR3).	[8]

References

• [1] Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3).Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13296-301. doi: 10.1073/pnas.0405354101. Epub 2004 Aug 24.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [4] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [5] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [6] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [7] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.